17-alpha-propadienyl-substituted steroids

ABSTRACT

1. A PROCESS FOR THE PREPARATION OF A 3-KETO-COMPOUND OF THE FORMULA 3-(O=),13-RA,17-(CH2=C=CH-),17-(HO-)GONA-4,9-DIENE WHEREIN RA IS ALKYL HAVING FROM 1 TO 3 CARBON ATOMS; WHICH COMPRISES (A) REACTING A 17A-ETHYLNYL-SUBSTITUTED COMPOUND OF THE FORMULA 3,17-DI(HO-),13-RA,17-(CH*C-)GONA-4,9-DIENE WHEREIN RA IS AS DEFINED ABOVE WITH A DIALKYLAMINO-METHANOL OF THE FORMULA HO-CH2-N(-R&#39;&#39;)-R&#34; WHEREIN EACH OF R&#39;&#39; AND R&#34; IS, INDEPENDENTLY, ALKYL HAVING FROM 1 TO 3 CARBON ATOMS; AND R&#39;&#39; AND R&#34; MAY BE JOINED TO FORM, IN CONJUNCTION WITH THE NITROGEN ATOM, A RING HAVING FROM 4 TO 6 CARBON ATOMS IN THE PRESENCE OF CUPROUS IONS AND ACETIC ACID AT TEMPERATURES OF FROM ABOUT 10: TO 80* C., IN AN INERT ORGANIC SOLVENT; TO OBTAIN A 17A-DIALKYLAMINO PROPYLNYL-SUBSTITUTED COMPOUND OF THE FORMULA 3,17-DI(HO-),13-RA,17-(R&#39;&#39;-N(-R&#34;)-CH2-C*C-)GONA-4,9-DIENE WHEREIN RA, R&#39;&#39; AND R&#34; ARE AS DEFINED ABOVE; (B) WHICH DIALKYLAMONOPROPYNYL-SUBSTITUTED COMPOUND IS THEN REACTED WITH A COMPOUND OF THE FORMULA   R&#39;&#39;&#34;-Y   WHEREIN R&#39;&#39;&#34; IS ALKYL HAVING FROM 1 TO 3 CARBON ATOMS; AND Y IS AN ANIONIC RESIDUE OF A MINERAL ACID OTHER THAN A FLUORIDE ION, OR RESIDUE IF A SULFONIC ACID, TO OBTAIN A QUATERNARY SALT OF THE FORMULA (3,17-DI(HO-),13-RA-GONA-4,9-DIEN-17-YL)-C*CWHEREIN RA, R&#39;&#39;, R&#34; AND R&#39;&#39;&#34; AND Y ARE AS DEFINED ABOVE; (C) WHICH QUATERNARY SALT IS REDUCED WITH A COMPLEX HYDRIDE TO OBTAIN A DIOL COMPOUND OF THE FORMULA 3,17-DI(HO-),13-RA,17-(CH2=C=CH-)GONA-4,9-DIENE WHEREIN RA IS AS DEFINED ABOVE; AND THE COMPLEX HYDRIDE IS A HYDRIDE ION SOURCE SELECTED FROM THE ROUP CONSISTING OF COMPOUNDS OF FORMULA Z(+) W1-M(-)(-H)(-W2)-W3 IN WHICH M REPRESENTS AN ALUMINUM GALLIUM OR BORON ATOM, Z REPRESENTS AN ALKALI METAL OR ALKALINE EARTH METAL ATOM, AND W1, W2 AND W3 WHICH MAY BE THE SAME OR DIFFERENT, EACH REPRESENTS A HYDROGEN ATOM, OR AN ALKYL OR ALKOXY CONTANING UP TO 6 CARBON ATOMS, OR AN ALKOXYALKOXY RADICAL WHEREIN THE ALKYL AND ALKYLENE PORTIONS EACH CONTAIN UP TO 6 CARBON ATOMS AND COMPOUNDS OF FORMULA W4-M(-H)-W5 CH2-N(+)(-R&#39;&#39;)(-R&#34;)-R&#34;&#39;&#39; . Y(-) IN WHICH M IS AS DEFINED ABOVE, AND W4 AND W5, WHICH MAY BE THE SAME OR DIFFERENT, EACH SIGNIFIES A HYDROGEN ATOM OR AN ALKYL RADICAL CONTAINING FROM 1 TO 6 CARBON ATOMS, (D) WHICH DIOL COMPOUND IS THEN OXIDIZED AT THE 3POSITION TO THE 3-KETO COMPOUND, AS DEFINED ABOVE, IN THE ORESENCE OF AN OXIDIZING AGENT WHICH IS SELECTED FROM THE GROUP CONSISTING OF A P-BENZOQUINONE, CHLORANIL, 2,3-DICHLORO-5,6-DICYANOBENZOQUINONE AND ACTIVATED MANGANESE DIOXIDE, AT FROM 10* TO 50*C. IN AN INERT SOLVENT.

United States Patent 3,842,104 17-ALPHA-PROPADIENYL-SUBSTITUTED STEROIDS Imre Bacso, Morristown, and Robert V. Coombs, Chatham, N .J.,assignors to Sandoz-Wander, Inc., Hanover,

No Drawing. Continuation-impart of abandoned application Ser. No. 69,929, Sept. 4, 1970. This application Apr. 17, 1972, Ser. No. 244,889

Int. Cl. C07c 169/22 US. Cl. 260397.4 12 Claims ABSTRACT OF THE DISCLOSURE 13-alkyl 17 ,H-hydroxy-17a-propadienylgona-4,5-dien- 3-ones are useful as pharmaceuticals and are obtainable by a multi-step procedure, which involves carrying out a Mannich-type reaction to convert a l7-a-ethynyl-substituted 4,9-dien-3,l7-B-diol steroid to its 17-a-dialkylaminopropynyl-substituted analog, which is then converted to a quaternary ammonium salt, which is then reduced using a complex metal hydride to obtain the corresponding 17- a-propadienyl-3,l7-B-diol product, which is then oxidized at the 3-position to obtain the corresponding 17-B-hydroxy- 3-keto-final product.

This is a continuation-in-part of copending application Ser. No. 69,929 filed Sept. 4, 1970, now abandoned.

This invention relates to steroidal compounds, and more particularly to the preparation of certain 17-a-propadienylsubstituted-4,9-dien steroidal compounds.

The final compounds obtainable by the process of this invention are represented by the formula I,

wherein R is alkyl having from 1 to 3 carbon atoms, e.g., methyl, ethyl, n-propyl and isopropyl; and preferably is unbranched.

The above-described compounds I are disclosed in the literature, e.g. Belgian Pat. 742,137, as being prepared by a process which employs a protected intermediate, i.e. in the form of a 3-ketal, e.g. ethylenedioxy, 9(11)-diene intermediate, which requires conversion by acid hydrolysis-rearrangement to the final product. The present invention provides a convenient and efiicient method for preparing compounds I in significantly improved yield and purity.

A process of this invention for the preparation of the above-described compounds I, may be conveniently represented by the following reaction scheme wherein R is as defined above, each of R and R is, independently, lower alkyl, e.g., having from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl and isopropyl, and is preferably unbranched; and R and R" may be joined to form, in conjunction with the nitrogen atom, a ring having from 4 to 6 carbon atoms, such as a pyrrolidino or piperidino or homopiperidino group; and, R' is lower alkyl, e.g., having from 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl and isopropyl and is preferably unbranched; and Y is the anionic residue of a mineral acid other than a fluoride ion; e.g. a monovalent ion of a halogen atom having an atomic weight of from 34 to 128; i.e., chloro, bromo, or iodo, or the residue of a sulfonic acid, e.g. of

3,842,104 Patented Oct. 15, 1974 "ice an alkylsulfonic acid such as a mesylate ion, or of an aromatic sulfonic acid, such as a tosylate ion, or the like. It will be noted in the reaction scheme that the geometric identity of the hydroxy group at the 3-carbon atom of ring A is immaterial to the procedure, as such hydroxy group is eventually oxidized to the carbonyl. Hence, the 30: or 35 isomers or a mixture thereof can be employed as the compound X.

Reaction Scheme With reference to the Reaction Scheme, Process step 0 is a condensation of a suitable 17a-ethyny1-17 8-hydroxy substituted steroid with a suitable dialkylamino-methanol. Process c can 'be carried out under conditions conventionally employed in carrying out Mannich reactions. Preferably, Process c is carried out in the presence of cuprous ions and small amounts of weak acid, (e.g., acetic acid), at temperatures of from about 10 to 80 C., preferably from about 40 to 70 C., in an inert organic solvent, such as dioxane or tetrahydrofuran. A preferred source of cuprous ion is cuprous chloride.

Process c involves the quaternization of a compound A with a reagent R"Y, to give the corresponding quaternary ammonium salt (compound B). The quaternization (process may be carried out in the conventional manner, e.g., in a suitable solvent, such as acetone, at a temperature of from -20 to +30 C. e.g. from 0 to 30 C.; neither the solvent nor the temperature conditions being critical. A preferred R"Y is methyl iodide.

In Processes c and c it is preferred that R', R" and R' are the same, and it is particularly preferred they are all methyl.

Process c is a reduction of a compound B with a complex hydride. Process 0 may be carried out in an organic medium which is not detrimental to the reaction. The complex hydride is suitably a hydride ion source selected from the group consisting of compounds of formula XI Wa XI in which M represents an aluminum, gallium or boron atom,

Z represents an alkali metal or alkaline earth metal atom,

e.g., Li, Na, K, Ca or Mg, and

W W and W which may be the same or different, each represents a hydrogen atom, or an alkyl or alkoxy containing up to 6 carbon atoms, or an alkoxyalkoxy radical wherein the alkyl and alkylene portions each contain up to 6 carbon atoms,

and compounds of formula XII in which M is as defined above, and

W and W which may be the same or different each signifies a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms,

Preferred hydride-ion sources for use in process c are those bearing at least two hydrogen atoms, e.g. lithium aluminum hydride, magnesium aluminium hydride, lithi um gallium hydride, diethyl aluminum hydride and sodium bis(2-methoxyethoxy) aluminum hydride; more preferably lithium aluminum hydride or sodium bis(2-methoxyethoxy) aluminum hydride.

The organic medium used in process c;, is preferably of an aprotic nature. Suitable media include cyclic and acyclic ethers, such as diethyl ether, tetrahydrofuran or dioxane and aromatic solvents such as benzene, toluene or pyridien or mixtures thereof, preferably pyridine.

The process c is preferably carried out at a temperature of from 80 to +80 0., most preferably from 10 to +50 C. It is preferred to exclude moisture from the reaction mixture.

Process c involves oxidizing the 3-hydroxy group of compound C with an oxidizing agent conventionally employed in oxidizing an allyclic secondary hydroxy group to a keto group, e.g., quinones such as p-benzoquinone, chloranil or 2,3 dichloro-5,G-dicyanobenzoquinone or activated manganese dioxide, e.g. at from 10 to 50 C., preferably at to 30 C. in an inert solvent e.g., a cyclic ether such as dioxane, or a tertiary alkanol, such as tbutanol.

In the above-described procedures, the starting materials and reagents are known and may be prepared by methods described in the literature, or where not known may be prepared in a manner analogous to that for preparing the known compounds. For example, the known compound 17a-ethynylestra-5 l0)-en-l7fi-ol-3-one may be converted to its 4,9 diene analog by treatment with pyridinium hydrobromide perbromide, i.e., 17a ethynylestra-4,9-dien- 17/8-ol-3-one, which upon reduction of the 3-carbonyl yields the corresponding compound X, i.e., a mixture of 17u-ethynylestra-4,9-diene-3a,17B and 3 ,8,17;3-diol.

The above-described compounds I are useful because they possess pharmacological properties in animals. In particular, such compounds are useful as fertility control agents in warm-blooded animals as they possess progestational activity as indicated by standard tests, such as the clauberg test, e.g., the method basically described in Endocrinology 63 1958) 464 wherein the rabbit is given 0.0025 to 1.0 milligram of active agent.

These compounds may be combined with a pharmaceutically acceptable carrier or adjuvant. They may be administered orally or parenterally. The dosage will vary depending upon the mode of administration utilized and the particular compound employed. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.0025 milligram to 30 milligrams. It will be appreciated by those skilled in the art, that the daily dosage level is independent of body weight. Dosage forms suitable for internal administration comprise from about 0.0025 milligram to about 30 milligrams of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

The compounds of formula I are also useful as menstrual function regulating agents and as estrus regulating and controlling agents. For the above mentioned uses the compounds of formula I may be administered alone in the manner and dosage described above, or in combination with a suitable estrogenic agent, the latter for example at a dosage of about 0.1 mg. For the regulation of the menstrual function, the estrogenic agent may be admixed with a compound of formula I, or alternatively the estrogenic agent may be administered alone in the first part of the menstrual cycle, and in admixture with the Compound of formula I in the latter days of the cycle.

A representative formulation suitable for oral administration is a tablet prepared by standard tabletting techniques which contain the following:

This invention is illustrated but not limited by the fol lowing example, wherein all temperatures are Centigrade and room temperature is 20 to 30 C., unless indicated otherwise.

Magnesium stearate EXAMPLE 17a-Pr0padienylestra4,9-dien-1 7;3-0l-3-0ne Step 1 Mixture of 17a-ethynylestra-4,9dien-3u,17/3 and 35,175- diol.225 g. of 17a ethynylestra-4,9-dien-l7 8-ol-3-one and 4.5 liters of dry methanol are charged to a vessel. 60 g. of sodium borohydride are added with stirring, at room temperature, portionwise over a period of 3 hours. Stirring is continued for an additional hour.

500 ml. of water are carefully added to the reaction mixture, the mixture concentrated under vacuum to 2 liters at 40 C., then poured into 4 liters of saturated aqueous sodium chloride and 4 liters of water. An oil containing the product separates, which oil is extracted with methylene chloride. The methylene chloride extracts are combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and then concentrated to obtain a mixture of 17a-ethynylestra- 4,9 diene 3a,l7;8-diol and 17a-enthynylestra-4,9-diene- 3/3,17fi-diol as an oil.

Step 2 17oz Dimethylaminopropynylestra-4,9-dien-3a,17p-and- 3B-17 8-diol.236 g. of mixture of 17a-ethynylestra-4,9- diene-3u,l7B-and-3B,17fidiol (obtained in Step 1), 2.25 liters of p-dioxane, 225 ml. of dimethylaminomethanol, 3.75 g. of cuprous chloride and 135 ml. of glacial acetic acid are charged to a vessel, and the mixture stirred, at 50 C. for 1.5 hours. 1.3 liters of the p-dioxane are removed by distilling under vacuum at 50 C. The resulting concentrate is then poured into a mixture of 6 liters of saturated aqueous sodium chloride and 2 liters of water. A solution of 165 g. of anhydrous potassium carbonate in 1 liter of water is then added thereto. The resulting mixture is then extracted with methylene chloride. The combined methylene chloride extracts are then washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, then concentrated under vacuum to about 3 liters, treated with charcoal, filtered, and the filtrate evaporated to a syrup. Residual p-dioxane is then removed under high vacuum to obtain a mixture of 17adimethylaminopropynylestra 4,9 diene-3a,17fl-and,313, 17,8-dio1 as an oil and is used in the next step (Step 3).

Step 3 Methiodide sa1t.265 g. of a mixture of 17a-dimethylaminopropynylestra-4,9-diene-3a,17 9-and-3,B,17,3diol and 2.65 liters of acetone are charged to a vessel and 265 ml. of methyl iodide are added dropwise over a period of about V2 hour, with stirring, resulting in formation of crystals of methiodide salt. Stirring is continued for an hour after addition of the methyl iodide has been completed. The crystals of the product are recovered by filtration, washed with ice-cold acetone, the acetone solvent removed under vacuum to obtain the methiodide, which is used for the next reaction step (Step 4).

Step 4 Mixture of 17a-propadienylestra-4,9-diene-3a,17,8-and- 3 8,17 8-diol.220 g. of the methiodide salt obtained in Step 3 and 6.6 liters of dry pyridine are charged to a vessel. 49 g. of lithium aluminum hydride is added portion-wise to the stirred mixture, at a rate such that the temperature of the mixture does not exceed about 50 C. The reaction mixture is then cooled to room temperature and 49 ml. of water, then 49 ml. of 15% aqeous sodium hydroxide solution, then 150 ml. of water are carefully added to the reaction mixture at a rate such that the temperature does not exceed 50 C. Solids are separated by filtration, then washed with pyridine. The filtrate and wash are combined and concentrated under vacuum to a syrup, which is then taken up in 1.5 liters of toluene. The toluene solvents is then removed by distilling under vacuum and the residue is then taken up in methylene chloride which is then washed with water, then saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and filtered. The methylene chloride solution is then concentrated to a syrup which is then taken up in 2 liters of acetone (any insolubles being filtered E). The acetone solvent is then removed under vacuum to obtain the product as an oil.

Step

17a propadienylestra-4,9-dien-17,8-ol-3-one.-138.0 g. of the mixture of 17a-propadieny1estra-4,9-diene-3a,175- and-3B,17fi-diol obtained in Step 4, and 1380 ml. of pdioxane are charged to a vessel. 125 g. of 2,3-dichloro- 5,6 dicyano-benzoquinone in 690 ml. of p-dioxane is slowly added thereto, the temperature of the mixture being maintained at about 30 C. After stirring for 1 hour at room temperature, 103.5 g. of anhydrous potassium carbonate and 44 g. of sodium dithionite in 1 liter of water is added while the temperature of the mixture is maintained at or below 30 C. The reaction mixture is then poured into 8 liters of saturated aqueous sodium chloride and extracted with ether. The ether extracts are combined, washed with saturated aqueous sodium chloride and then evaporated under high vacuum to obtain an oily residue. The residue is taken up in ether and the ether solution is passed through an aluminum oxide column to yield the product, i.e. 17a propadienylestra-4,9-dien-1713-01-3- one, m.p. Ill-113 C.

Carrying out the procedure of Step 4 but using in place of the pyridine used therein, a like volume of benzene/ tetrahydrofuran (1:1); and in place of the lithium aluminum hydrodie used therein, an equivalent amount of sodium bis(2 methoxyethoxy) aluminum hydride, there is similarly obtained a mixture of 17a-propadienylestra-4,9- diene-3a,17/8 and 3fl,17fl-diol.

What is claimed is:

1. A process for the preparation of a 3-keto-c0mpound of the formula wherein R is alkyl having from 1 to 3 carbon atoms;

which comprises (a) reacting a 17a-ethynyl-substituted compound of the formula wherein R is as defined above with a dialkylamino-methanol of the formula wherein each of R and R" is, independently, alkyl having from 1 to 3 carbon atoms; and R and R" may be joined to form, in conjunction with the nitrogen atom, a ring having from 4 to 6 carbon atoms in the presence of cuprous ions and acetic acid at temperatures of from about 10 to C., in an inert organic solvent;

to obtain a 17a-dialkylamino propynyl-substituted compound of the formula wherein R, R and R" are as defined above;

'(b) which dialkylaminopropynyl-substituted compound is then reacted with a compound of the formula I!I Y wherein R" is alkyl having from 1 to 3 carbon atoms; and Y is an anionic residue of a mineral acid other than a fluoride ion, or residue of a sulfonic acid, to obtain a quaternary salt of the formula wherein R", R, R" and R' and Y are as defined above; (c) which quaternary salt is reduced with a complex hydride to obtain a diol compound of the formula wherein R is as defined above; and the complex hydride is a hydride ion source selected from the group consisting of compounds of formula W2 2 wr-llrin in which M represents an aluminum, gallium or boron atom, Z represents an alkali metal or alkaline earth metal atom, and W W and W which may be the same or dif ferent, each represents a hydrogen atom, or an alkyl or alkoxy containing up to 6 carbon atoms, or an alkoxyalkoxy radical wherein the alkyl and alkylene portions each contain up to 6 carbon atoms and compounds of formula W4 W5-l\ 'I-H in which M is as defined above, and W and W which may be the same or different, each signifies a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms, (d) which diol compound is then oxidized at the 3- position to the 3-keto compound, as defined above, in the presence of an oxidizing agent which is selected from the group consisting of p-benzoquinone, chloranil, 2,3-dichloro-5,6-dicyanobenzoquinone and activated manganese dioxide, at from to 50 C., in an inert solvent. 2. A process of Claim 1 wherein each of R, R, R" and R' is methyl, and Y is iodo.

3. A process of Claim 2 in which the oxidizing agent is 2,3-dichloro-5,6-dicyanobenzoquinone.

4. A process of Claim 3 wherein the complex hydride is lithium aluminum hydride.

5. A process-of Claim 3 wherein the complex hydride is sodium bis(2-methoxyethoxy) aluminum hydride.

8 6. A process for preparing a compound of the formula OH R! wherein R is alkyl having from 1 to 3 carbon atoms; and each of R and R" is, independently, alkyl having from 1 to 3 carbon atoms; and R and R" may be joined to form, in conjunction with the nitrogen atom, a ring having from 4 to 6 carbon atoms which comprises reacting a steroidal compound of the formula on I if-(Eon wherein R is as defined above, with a dialkylaminomethanol compound of the formula wherein R is alkyl having from 1 to 3 carbon atoms; and each of R and R" is, independently, alkyl having from 1 to 3 carbon atoms; and R and R" may be joined to form, in conjunction with the nitrogen atom, a ring having from 4 to 6 carbon atoms; R is alkyl having from 1 to 3 carbon atoms; and Y is an anionic residue of a mineral acid other than a fluoride ion, or residue of a sulfonic acid,

which comprises (a) reacting a 17a-ethynyl-substituted compound of the formula wherein R is as defined above with a dialkylamino-methanol of the formula (b) which dialkylaminopropynyl-substituted compound is subsequently reacted with a compound of HO CH' N\ the formula R R!!I Y wherein R' and Y are as defined above to obtain wherein R and R" are defined above, in the the quaternary ammonium Salt presence of cuprous ions and acetic acid at tem- 9 A process of Claim 3 wherein each f Re peratures of from about 10 to 80 C., in an and is methyl and Y is iodo inert Organic Solvent; 10. A process of Claim 1 wherein R is methyl. 10 11. A process of Claim 6 wherein R is methyl. to obtain a 17a-d1a1ky1armnopropynyl-substituted com- 12. A process of Claim 8 wherein Ra is methyL pound of the formula References Cited OH UNITED STATES PATENTS Ra| 3,392,166 7/1968 Edwards et a1. 260239.55 T 3,423,404 1/1969 Klimstra 260-239.55 3,424,768 1/1969 Klimstra 260397.5 3,681,411 8/1972 Crabbe et a1. 260397.4 20 3,682,985 8/ 1972 Bacso et a1. 260397.4 o 3,658,854 4/1972 Fried 260-3975 f HENRY A. FRENCH, Primary Examiner 11 US. 01. X.R.

wherein R R and R" are as defined above; 397's; 424 243 

1. A PROCESS FOR THE PREPARATION OF A 3-KETO-COMPOUND OF THE FORMULA 3-(O=),13-RA,17-(CH2=C=CH-),17-(HO-)GONA-4,9-DIENE WHEREIN RA IS ALKYL HAVING FROM 1 TO 3 CARBON ATOMS; WHICH COMPRISES (A) REACTING A 17A-ETHYLNYL-SUBSTITUTED COMPOUND OF THE FORMULA 3,17-DI(HO-),13-RA,17-(CH*C-)GONA-4,9-DIENE WHEREIN RA IS AS DEFINED ABOVE WITH A DIALKYLAMINO-METHANOL OF THE FORMULA HO-CH2-N(-R'')-R" WHEREIN EACH OF R'' AND R" IS, INDEPENDENTLY, ALKYL HAVING FROM 1 TO 3 CARBON ATOMS; AND R'' AND R" MAY BE JOINED TO FORM, IN CONJUNCTION WITH THE NITROGEN ATOM, A RING HAVING FROM 4 TO 6 CARBON ATOMS IN THE PRESENCE OF CUPROUS IONS AND ACETIC ACID AT TEMPERATURES OF FROM ABOUT 10: TO 80* C., IN AN INERT ORGANIC SOLVENT; TO OBTAIN A 17A-DIALKYLAMINO PROPYLNYL-SUBSTITUTED COMPOUND OF THE FORMULA 3,17-DI(HO-),13-RA,17-(R''-N(-R")-CH2-C*C-)GONA-4,9-DIENE WHEREIN RA, R'' AND R" ARE AS DEFINED ABOVE; (B) WHICH DIALKYLAMONOPROPYNYL-SUBSTITUTED COMPOUND IS THEN REACTED WITH A COMPOUND OF THE FORMULA 